tbuckley/cabot-search huggingface dataset:
<i>ATM</i> Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Natalie I. Vokes, Ana Galan Cobo, Margarita Fernandez-Chas, David Molkentine, Santiago Treviño, Vitaly Druker, Yu Qian, Sonia Patel, Stephanie Schmidt, Lingzhi Hong, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J. Jack Lee, Marcelo V. Negrao, Don L. Gibbons, Ara Vaporciyan, Xiuning Le, Jia Wu, Jianjun Zhang, Una Rigney, Sonia Iyer, Emma Dean, John V. Heymach
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non–small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated. Experimental Design: Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models. Results: Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q &amp;lt; 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy. Conclusions: ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.
Three synchronous lesions with different historical types diagnosed by endoscopic submucosal dissection in one patient
Authors: Xue Chen, Benyan Zhang, Qi Sun, Xi Chen
Journal: Endoscopy (2023)

A 69-year-old man underwent gastroscopy owing to intermittent abdominal distension for over 4 months. The gastroscopy revealed two distinct lesions in the lower stomach body, which was highly atrophied (O-3) [1], and the background mucosa was infected with Helicobacter pylori. Lesion 1, labeled as 0-Is + IIa [2], measured 40 × 20 mm and had a nodular mixed-type appearance on the posterior wall of the stomach body ([Fig. 1 a, b]). Lesion 2, labeled as 0-IIb, measured 15 × 10 mm and was adjacent to lesion 1 on the oral side ([Fig. 2 a]). Biopsy pathology of both lesions showed atypical cells.
Kill two birds with one stone: one submucosal tunnel for achalasia combined with large epiphrenic diverticulum
Authors: Jingjing Lian, Aiping Xu, Tao Chen, Meidong Xu
Journal: Endoscopy (2023)

Esophageal epiphrenic diverticulum (EED) in the distal 10 cm of the esophagus usually occurs in patients with esophageal motility disorders including achalasia. Per-oral endoscopic myotomy (POEM) is an effective and minimally invasive method that has developed into an important treatment for achalasia [1]. In 2016, we created submucosal tunneling endoscopic septum division (STESD) as a novel technique for treating Zenker's diverticulum [2]. Here we present a case of achalasia with a large epiphrenic diverticulum that we cured with POEM and STESD together using only one submucosal tunnel.
Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase
Authors: Julia Hummel, Charlotte Benkendorff, Louise Fritsche, Katsiaryna Prystupa, Andreas Vosseler, Sofiya Gancheva, Sandra Trenkamp, Andreas L. Birkenfeld, Hubert Preissl, Michael Roden, Hans-Ulrich Häring, Andreas Fritsche, Andreas Peter, Robert Wagner, Stephanie Kullmann, Martin Heni
Journal: Nature Metabolism (2023)

Insulin action in the human brain modulates eating behaviour, whole-body metabolism and body fat distribution1,2. In particular, brain insulin action increases whole-body insulin sensitivity, but these studies were mainly performed in lean men3,4. Here we investigate metabolic and hypothalamic effects of brain insulin action in women with a focus on the impact of menstrual cycle ( ClinicalTrials.gov registration: NCT03929419 ).Eleven women underwent four hyperinsulinemic-euglycemic clamps, two in the follicular phase and two in the luteal phase. Brain insulin action was introduced using nasal insulin spray5-7 and compared to placebo spray in a fourfold crossover design with change in glucose infusion rate as the primary endpoint. Here we show that during the follicular phase, more glucose has to be infused after administration of nasal insulin than after administration of placebo. This remains significant after adjustment for blood glucose and insulin. During the luteal phase, no significant influence of brain insulin action on glucose infusion rate is detected after adjustment for blood glucose and insulin (secondary endpoint). In 15 other women, hypothalamic insulin sensitivity was assessed in a within-subject design by functional magnetic resonance imaging with intranasal insulin administration8. Hypothalamus responsivity is influenced by insulin in the follicular phase but not the luteal phase.Our study therefore highlights that brain insulin action improves peripheral insulin sensitivity also in women but only during the follicular phase. Thus, brain insulin resistance could contribute to whole-body insulin resistance in the luteal phase of the menstrual cycle.
Endoscopic treatment of bile duct stones after bariatric Roux-en-Y gastric bypass through endoscopic ultrasound-directed transgastric ERCP
Authors: Francisco Vara-Luiz, Gonçalo Nunes, Pedro Pinto-Marques, Carla Oliveira, Ivo Mendes, Marta Patita, Jorge Fonseca
Journal: Endoscopy (2023)

Endoscopic retrograde cholangiopancreatography (ERCP) is technically challenging after Roux-en-Y gastric bypass (RYGB) [1]. Standard approaches include enteroscopy-assisted and laparoscopy-assisted ERCP, which present difficult implementation in clinical practice [2]. The authors report endoscopic ultrasound-directed transgastric ERCP (EDGE) for the treatment of bile duct stones in RYGB patients ([Video 1]).
Personalized Medicine's Coming of Age: One Drug, One Patient
Authors: Muzaffar H. Qazilbash, Larry W. Kwak
Journal: Clinical Cancer Research (2023)

Summary A dendritic cell/myeloma fusion vaccine, given with lenalidomide and GM-CSF, did not result in a statistically significant increase in CR rates at 1 year posttransplant but was associated with a significant increase in circulating multiple myeloma–reactive lymphocytes indicative of tumor-specific immunity. See related article by Chung et al., p. 4784
Smart capsules for sensing and sampling the gut: status, challenges and prospects
Authors: Muhammad Rehan, Ibrahim Al-Bahadly, David G Thomas, Wayne Young, Leo K Cheng, Ebubekir Avci
Journal: Gut (2023)

Smart capsules are developing at a tremendous pace with a promise to become effective clinical tools for the diagnosis and monitoring of gut health. This field emerged in the early 2000s with a successful translation of an endoscopic capsule from laboratory prototype to a commercially viable clinical device. Recently, this field has accelerated and expanded into various domains beyond imaging, including the measurement of gut physiological parameters such as temperature, pH, pressure and gas sensing, and the development of sampling devices for better insight into gut health. In this review, the status of smart capsules for sensing gut parameters is presented to provide a broad picture of these state-of-the-art devices while focusing on the technical and clinical challenges the devices need to overcome to realise their value in clinical settings. Smart capsules are developed to perform sensing operations throughout the length of the gut to better understand the body’s response under various conditions. Furthermore, the prospects of such sensing devices are discussed that might help readers, especially health practitioners, to adapt to this inevitable transformation in healthcare. As a compliment to gut sensing smart capsules, significant amount of effort has been put into the development of robotic capsules to collect tissue biopsy and gut microbiota samples to perform in-depth analysis after capsule retrieval which will be a game changer for gut health diagnosis, and this advancement is also covered in this review. The expansion of smart capsules to robotic capsules for gut microbiota collection has opened new avenues for research with a great promise to revolutionise human health diagnosis, monitoring and intervention.
Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis
Authors: Yanru Ma, Xinyu Zhang, Baoqin Xuan, Danjie Li, Nan Yin, Lijun Ning, Yi-Lu Zhou, Yuqing Yan, Tianying Tong, Xiaoqiang Zhu, Xiaowen Huang, Muni Hu, Zhenhua Wang, Zhe Cui, Huabin Li, Jiqiu Wang, Jing-Yuan Fang, Ruixin Liu, Haoyan Chen, Jie Hong
Journal: Gut (2023)

Background and aims Deregulation of RNA N6-methyladenosine (m 6 A) modification in intestinal epithelial cells (IECs) influences intestinal immune cells and leads to intestinal inflammation. We studied the function of fat mass-and obesity-associated protein (FTO), one of the m 6 A demethylases, in patients with ulcerative colitis (UC). Methods We analysed colon tissues of Fto flox/flox ; Villin-cre mice and their Fto flox/flox littermates with dextran sulfate sodium (DSS) using real-time PCR and 16s rRNA sequencing. RNA and methylated RNA immunoprecipitation sequencing were used to analyse immunocytes and IECs. Macrophages were treated with conditioned medium of FTO-knockdown MODE-K cells or sphingosine-1-phosphate (S1P) and analysed for gene expression. Liquid chromatograph mass spectrometry identified C 16 -ceramide. Results FTO downregulation was identified in our in-house cohort and external cohorts of UC patients. Dysbiosis of gut microbiota, increased infiltration of proinflammatory macrophages, and enhanced differentiation of Th17 cells were observed in Fto flox/flox ;Villin-cre mice under DSS treatment. FTO deficiency resulted in an increase in m 6 A modification and a decrease in mRNA stability of CerS6, the gene encoding ceramide synthetase, leading to the downregulation of CerS6 and the accumulation of S1P in IECs. Subsequentially, the secretion of S1P by IECs triggered proinflammatory macrophages to secrete serum amyloid A protein 1/3, ultimately inducing Th17 cell differentiation. In addition, through bioinformatic analysis and experimental validation, we identified UC patients with lower FTO expression might respond better to vedolizumab treatment. Conclusions FTO downregulation promoted UC by decreasing CerS6 expression, leading to increased S1P accumulation in IECs and aggravating colitis via m 6 A-dependent mechanisms. Lower FTO expression in UC patients may enhance their response to vedolizumab treatment.
Updates to the modern diagnosis of GERD: Lyon consensus 2.0
Authors: C Prakash Gyawali, Rena Yadlapati, Ronnie Fass, David Katzka, John Pandolfino, Edoardo Savarino, Daniel Sifrim, Stuart Spechler, Frank Zerbib, Mark R Fox, Shobna Bhatia, Nicola de Bortoli, Yu Kyung Cho, Daniel Cisternas, Chien-Lin Chen, Charles Cock, Albis Hani, Jose Maria Remes Troche, Yinglian Xiao, Michael F Vaezi, Sabine Roman
Journal: Gut (2023)

The Lyon Consensus provides conclusive criteria for and against the diagnosis of gastro-oesophageal reflux disease (GERD), and adjunctive metrics that consolidate or refute GERD diagnosis when primary criteria are borderline or inconclusive. An international core and working group was assembled to evaluate research since publication of the original Lyon Consensus, and to vote on statements collaboratively developed to update criteria. The Lyon Consensus 2.0 provides a modern definition of actionable GERD, where evidence from oesophageal testing supports revising, escalating or personalising GERD management for the symptomatic patient. Symptoms that have a high versus low likelihood of relationship to reflux episodes are described. Unproven versus proven GERD define diagnostic strategies and testing options. Patients with no prior GERD evidence (unproven GERD) are studied using prolonged wireless pH monitoring or catheter-based pH or pH-monitoring off antisecretory medication, while patients with conclusive GERD evidence (proven GERD) and persisting symptoms are evaluated using pH-impedance monitoring while on optimised antisecretory therapy. The major changes from the original Lyon Consensus criteria include establishment of Los Angeles grade B oesophagitis as conclusive GERD evidence, description of metrics and thresholds to be used with prolonged wireless pH monitoring, and inclusion of parameters useful in diagnosis of refractory GERD when testing is performed on antisecretory therapy in proven GERD. Criteria that have not performed well in the diagnosis of actionable GERD have been retired. Personalisation of investigation and management to each patient's unique presentation will optimise GERD diagnosis and management.
Automatic analysis of bronchus-artery dimensions to diagnose and monitor airways disease in cystic fibrosis
Authors: Qianting Lv, Leticia Gallardo-Estrella, Eleni-Rosalina Andrinopoulou, Yuxin Chen, Jean-Paul Charbonnier, Rikke Mulvad Sandvik, Daan Caudri, Kim Gjerum Nielsen, Marleen de Bruijne, Pierluigi Ciet, Harm Tiddens
Journal: Thorax (2023)

Background Cystic fibrosis (CF) lung disease is characterised by progressive airway wall thickening and widening. We aimed to validate an artificial intelligence-based algorithm to assess dimensions of all visible bronchus-artery (BA) pairs on chest CT scans from patients with CF. Methods The algorithm fully automatically segments the bronchial tree; identifies bronchial generations; matches bronchi with the adjacent arteries; measures for each BA-pair bronchial outer diameter (B out ), bronchial lumen diameter (B in ), bronchial wall thickness (B wt ) and adjacent artery diameter (A); and computes B out /A, B in /A and B wt /A for each BA pair from the segmental bronchi to the last visible generation. Three datasets were used to validate the automatic BA analysis. First BA analysis was executed on 23 manually annotated CT scans (11 CF, 12 control subjects) to compare automatic with manual BA-analysis outcomes. Furthermore, the BA analysis was executed on two longitudinal datasets (Copenhagen 111 CTs, ataluren 347 CTs) to assess longitudinal BA changes and compare them with manual scoring results. Results The automatic and manual BA analysis showed no significant differences in quantifying bronchi. For the longitudinal datasets the automatic BA analysis detected 247 and 347 BA pairs/CT in the Copenhagen and ataluren dataset, respectively. A significant increase of 0.02 of B out /A and B in /A was detected for Copenhagen dataset over an interval of 2 years, and 0.03 of B out /A and 0.02 of B in /A for ataluren dataset over an interval of 48 weeks (all p&lt;0.001). The progression of 0.01 of B wt /A was detected only in the ataluren dataset (p&lt;0.001). BA-analysis outcomes showed weak to strong correlations (correlation coefficient from 0.29 to 0.84) with manual scoring results for airway disease. Conclusion The BA analysis can fully automatically analyse a large number of BA pairs on chest CTs to detect and monitor progression of bronchial wall thickening and bronchial widening in patients with CF.
Novel electromagnetic navigation bronchoscopy system for the diagnosis of peripheral pulmonary nodules: a prospective, multicentre study
Authors: Ying Li, Wei Chen, Fangfang Xie, Rui Huang, Xiang Liu, Yang Xiao, Liming Cao, Yi Hu, Mingyao Ke, Shiman Wu, Jiayuan Sun
Journal: Thorax (2023)

Background Traditional electromagnetic navigation bronchoscopy (ENB) is a real-time image-guided system and used with thick bronchoscopes for the diagnosis of peripheral pulmonary nodules (PPNs). A novel ENB that could be used with thin bronchoscopes was developed. This study aimed to evaluate the diagnostic yield and the experience of using this ENB system in a real clinical scenario. Methods This multicentre study enrolled consecutive patients with PPNs adopting ENB from March 2019 to August 2021. ENB was performed with different bronchoscopes, ancillary techniques and sampling instruments according to the characteristics of the nodule and the judgement of the operator. The primary endpoint was the diagnostic yield. The secondary endpoints included the diagnostic yield of subgroups, procedural details and complication rate. Results In total, 479 patients with 479 nodules were enrolled in this study. The median lesion size was 20.9 (IQR, 15.9–25.9) mm. The overall diagnostic yield was 74.9% (359/479). A thin bronchoscope was used in 96.2% (461/479) nodules. ENB in combination with radial endobronchial ultrasound (rEBUS), a guide sheath (GS) and a thin bronchoscope was the most widely used guided method, producing a diagnostic yield of 74.1% (254/343). The median total procedural time was 1325.0 (IQR, 1014.0–1676.0) s. No severe complications occurred. Conclusion This novel ENB system can be used in combination with different bronchoscopes, ancillary techniques and sampling instruments with a high diagnostic yield and safety profile for the diagnosis of PPNs, of which the combination of thin bronchoscope, rEBUS and GS was the most common method in clinical practice. Trial registration number NCT03716284 .
Reduced-dose versus high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: predefined 2-year follow-up study
Authors: Shunsuke Furuta, Daiki Nakagomi, Yoshihisa Kobayashi, Masaki Hiraguri, Takao Sugiyama, Koichi Amano, Takeshi Umibe, Hajime Kono, Kazuhiro Kurasawa, Yasuhiko Kita, Ryutaro Matsumura, Yuko Kaneko, Keita Ninagawa, Keiju Hiromura, Shin-ichiro Kagami, Yosuke Inaba, Hideki Hanaoka, Kei Ikeda, Hiroshi Nakajima
Journal: Annals of the Rheumatic Diseases (2023)

Objectives The LoVAS trial reported non-inferiority in remission induction rates between the reduced-dose and conventional high-dose glucocorticoid regimens plus rituximab for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 6 months; however, maintenance glucocorticoid requirements and long-term outcomes are unknown. Methods A total of 140 patients with new-onset ANCA-associated vasculitis without severe glomerulonephritis or alveolar haemorrhage were randomised to receive reduced-dose prednisolone (0.5 mg/kg/day) plus rituximab (375 mg/m 2 /week×4) or high-dose prednisolone (1 mg/kg/day) plus rituximab. After achieving remission, patients received the rituximab maintenance therapy (1 g/6 months). Results A total of 134 patients were analysed. Among patients who achieved remission with the protocolised treatments, the majority of patients in the reduced-dose group (89.7%) and 15.5% in the high-dose group discontinued prednisolone (median time to withdrawal, 150 and 375 days, respectively). During 24-month trial period, two patients in the reduced-dose group (2.8%) died, while five patients in the high-dose group (7.6%) died (p=0.225). Relapse occurred in nine patients in the reduced-dose group (13.0%) (two major and seven minor) and five in the high-dose group (7.6%) (two major and three minor) (p=0.311). Serious adverse events (SAEs) were less frequent in the reduced-dose group (36 events in 19 patients, 27.5%) than in the high-dose group (54 events in 30 patients, 46.2%) (p=0.025). Conclusion At 24 months, frequencies of relapse did not differ between the groups, and SAEs were less frequent in the reduced-dose group due to the lower event rate in the 6-month induction phase. The bias to myeloperoxidase-ANCA positivity (85.8%) in the trial population should be noted. Trial registration number NCT02198248 .
Somatostatin neurons in prefrontal cortex initiate sleep-preparatory behavior and sleep via the preoptic and lateral hypothalamus
Authors: Kyoko Tossell, Xiao Yu, Panagiotis Giannos, Berta Anuncibay Soto, Mathieu Nollet, Raquel Yustos, Giulia Miracca, Mikal Vicente, Andawei Miao, Bryan Hsieh, Ying Ma, Alexei L. Vyssotski, Tim Constandinou, Nicholas P. Franks, William Wisden
Journal: Nature Neuroscience (2023)

The prefrontal cortex (PFC) enables mammals to respond to situations, including internal states, with appropriate actions. One such internal state could be 'tiredness'. Here, using activity tagging in the mouse PFC, we identified particularly excitable, fast-spiking, somatostatin-expressing, γ-aminobutyric acid (GABA) (PFC
Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda
Authors: Robert J Zupko, Tran Dang Nguyen, J Claude S Ngabonziza, Michee Kabera, Haojun Li, Thu Nguyen-Anh Tran, Kien Trung Tran, Aline Uwimana, Maciej F Boni
Journal: Nature Medicine (2023)

Artemisinin combination therapies (ACTs) are highly effective at treating uncomplicated Plasmodium falciparum malaria, but the emergence of the new pfkelch13 R561H mutation in Rwanda, associated with delayed parasite clearance, suggests that interventions are needed to slow its spread. Using a Rwanda-specific spatial calibration of an individual-based malaria model, we evaluate 26 strategies aimed at minimizing treatment failures and delaying the spread of R561H after 3, 5 and 10 years. Lengthening ACT courses and deploying multiple first-line therapies (MFTs) reduced treatment failures after 5 years when compared to the current approach of a 3-d course of artemether-lumefantrine. The best among these options (an MFT policy) resulted in median treatment failure counts that were 49% lower and a median R561H allele frequency that was 0.15 lower than under baseline. New approaches to resistance management, such as triple ACTs or sequential courses of two different ACTs, were projected to have a larger impact than longer ACT courses or MFT; these were associated with median treatment failure counts in 5 years that were 81-92% lower than the current approach. A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.